Abstract Introduction Suvorexant, an orexin receptor antagonist, improved total sleep time (TST) in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer’s disease (AD) and insomnia. The study included a pilot evaluation of an actigraphy watch for continuously recording patient’s sleep and daytime activity. We report on the utility of the watch for assessing sleep in relation to gold-standard PSG. Methods This was a randomized, double-blind, 4-week trial (ClinicalTrials.gov NCT02750306). Participants who met diagnostic criteria for both probable AD dementia and insomnia were randomized to suvorexant 10-20mg or placebo. Overnight sleep laboratory PSG was performed on 3 nights: screening, baseline, and Night-29 (last dose). An actigraphy watch (Garmin vívosmart® HR) was worn continuously by the patient. Separate analyses were performed for PSG and watch. We compared treatment effects on change-from-baseline in PSG-TST at Night-29 and WATCH-TST at Week-4 (average TST per night over Week-4). We also analyzed Night-29 data only with watch data restricted to the PSG recording time. Results A total of 274 participants were included in the Night-29 PSG analysis (suvorexant=135, placebo=139) and 223 in the Week-4 watch analysis (suvorexant=113, placebo=110). Suvorexant improved Night-29 PSG-TST by 28 minutes versus placebo (p=0.001) and Week-4 WATCH-TST by 17 minutes versus placebo (p=0.144). In the subgroup who had usable data for both assessments at Night-29 (suvorexant=57, placebo=50), the watch overestimated TST compared to PSG (e.g. placebo baseline scores = 412 minutes for WATCH-TST and 265 minutes for PSG-TST) and underestimated change-from-baseline treatment effects: the suvorexant versus placebo difference was 35 minutes for PSG-TST (p=0.057) and 20 minutes for WATCH-TST (p=0.405). Conclusion The watch was less sensitive than PSG for evaluating treatment effects on TST. However, results obtained with the watch were directionally similar to PSG in indicating a benefit of suvorexant versus placebo for improving TST in AD patients with insomnia. Support Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Abstract Introduction Suvorexant, an orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, improved total sleep time (TST) in a sleep laboratory polysomnography (PSG) study of patients with AD and insomnia. Here we report on the effects of suvorexant on sleep architecture in the study. Methods This was a randomized, double-blind, 4-week trial (ClinicalTrials.gov NCT02750306). Participants who met diagnostic criteria for both probable AD dementia (of mild to moderate severity) and insomnia were randomized to suvorexant 10mg (could be increased to 20mg based on clinical response) or matching placebo. Overnight sleep laboratory PSG was performed on 3 nights: screening, baseline, and Night-29 (last night of dosing). Suvorexant differences from placebo in changes-from-baseline at Night-29 for sleep architecture were analyzed as exploratory endpoints. Results A total of 274 participants were included in the analysis (suvorexant N=135, placebo N=139). At Night-29, suvorexant improved TST by 28 minutes versus placebo (p=0.001). There were no significant differences between suvorexant and placebo in the % of TST spent in REM (1.3%, 95% CI: -0.5, 3.0), N1 (0.6%, 95% CI: -1.2, 2.5), N2 (-1.0%, 95% CI: -3.2, 1.2), or N3 (-0.6%, 95% CI: -1.8, 0.6). There was no significant difference between suvorexant and placebo in latency to REM (-5.4 minutes, 95% CI: -23.4, 12.7). Conclusion Suvorexant improves TST without altering the underlying sleep architecture in AD patients with insomnia. Support Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Objective: To assess the performance of a Patient Global Impressions-Severity (PGI-S) scale for assessing insomnia severity. Background: The PGI-S was used as a patient self-assessment of insomnia severity in the development program for suvorexant, an orexin receptor antagonist approved for treating insomnia. Design/Methods: The analysis was based on data from two similarly designed randomized, double-blind, placebo-controlled, 3-month Phase 3 clinical trials in patients with DSM-IV criteria insomnia. Patients assessed insomnia severity during the previous week using the PGI-S, a 1-item questionnaire containing six response options ranging from 0 (none) to 5 (very severe), at the end of a baseline period and at the end of Week 2, and Months 1, 2, and 3. The Insomnia Severity Index (ISI) and other subjective and objective assessments were also completed by patients. PGI-S responses were compared primarily with the ISI using descriptive statistics and correlations to evaluate the following measurement characteristics of the PGI-S: concurrent criterion validity, construct validity, convergent validity, divergent validity, reliability, responsiveness, sensitivity, and clinically meaningful differences. Results: PGI-S scores decreased from baseline to Month 3 in a similar pattern to the ISI total score, and the Spearman correlation coefficient between PGI-S and the ISI was 0.80. Conclusions: Comparisons between the PGI-S and the ISI, a gold standard subjective measure, confirmed the benefit of suvorexant for patients with insomnia, and indicated that patients can rate their insomnia fairly well with the PGI-S, a simple, well-known, single-item rating scale. Study Supported by: Merck & Co., Inc., Kenilworth, NJ USA Disclosure: Dr. Herring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Herring has received compensation for serving on the Board of Directors of Merck & Co., Inc. Dr. Snyder has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Snyder has received compensation for serving on the Board of Directors of Merck & Co., Inc. Dr. Tao has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Tao has received compensation for serving on the Board of Directors of Merck & Co., Inc. Dr. Svetnik has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Svetnik has received compensation for serving on the Board of Directors of Merck & Co., Inc. Dr. Lines has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck & Co., Inc. Dr. Lines has received compensation for serving on the Board of Directors of Merck & Co., Inc.

Objective: To evaluate the efficacy and tolerability of rizatriptan versus placebo in pediatric migraineurs. Background Acute migraine treatment options for children are limited because it has been difficult to demonstrate efficacy over placebo in trials. Design/Methods: Children, ages 6-17yrs, who had not, historically, achieved satisfactory response to treatment with NSAIDs/acetaminophen, were enrolled in a novel design utilizing a single-blind run-in phase, followed by randomization into a double-blind, placebo-controlled phase with weight-based rizatriptan dosing (5-mg for Results: 702 patients 12-17yrs of age treated, with 570 evaluable for efficacy. Rizatriptan demonstrated a significantly higher response rate compared to placebo for pain-freedom at 2hrs in 12-17yr-olds: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio=1.55 [95% CI: 1.06, 2.26], p-value=0.025. The incidences of adverse events within 14-days postdose in 12-17yr-olds were similar between rizatriptan and placebo: 81/337 (24.0%) versus 83/365 (22.7%). 977 patients 6-17yrs of age treated during the study, with 770 evaluable for efficacy; the pattern of findings was similar to 12-17yr-olds. Conclusions: Rizatriptan was statistically significantly more effective than placebo in eliminating pain and generally well-tolerated in pediatric migraineurs. Supported by: Merck & Co., Inc. Disclosure: Dr. Ho has received personal compensation for activities with Merck & Co., Inc. as an employee.Dr. Ho holds stock and/or stock options in Merck & Co., Inc. Dr. Pearlman has received personal compensation for activities with GSK, Merck, Allergan, and Nautilus Pharmaceuticals as a consultant.Dr. Pearlman has received research support from GSK, Merck, and AstraZenenca. Dr. Lewis has received personal compensation for activities with Merck, Astra Zeneca, and GlaxoSmithKline.Dr. Lewis has received research support from Abbott, Astra Zeneca, Almirall, GlaxoSmithKline, Merck, and Ortho-McNeil. Dr. Hamalainen has received personal compensation for activities with Merck. Ms. Connor has received personal compensation for activities with Merck & Co., Inc. Ms. Connor holds stock and/or stock options in Merck & Co., Inc. Dr. Michelson has nothing to disclose. Dr. Zhang has received personal compensation for activities with Merck & Co., Inc. Dr. Harper-Mozley has received personal compensation for activities with Merck as an employee.Dr. Harper-Mozley holds stock and/or stock options in Merck. Ms. Strickler has received personal compensation for activities with Merck & Co., Inc., as an employee. Ms. Strickler holds stock and/or stock options in Merck & Co., Inc. Mr. Bachman has received personal compensation for activities with Merck & Co., Inc. as an employee. Mr. Bachman holds stock and/or stock options in Merck & Co., Inc. Dr. Mahoney has received personal compensation for activities with Merck & Co, Inc. as an employee. Dr. Mahoney holds stock and/or stock options in Merck & Co, Inc. Dr. Lines has received personal compensation for activities with Merck as an employee.Dr. Lines holds stock and/or stock options in Merck. Dr. Hewitt has received personal compensation for activities with Merck & Co., Inc. as an employee.

BACKGROUND:The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist.METHODS:Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports.RESULTS:Telcagepant 300 mg was more effective (p <or= 0.001) than placebo on all primary endpoints and the key secondary endpoint, as was telcagepant 150 mg (p <or= 0.05). Telcagepant 300 mg showed a slight numeric advantage over telcagepant 150 mg on most measures. Telcagepant 50 mg values were numerically intermediate between placebo and telcagepant 150 mg and 300 mg. The percentages of patients with adverse experiences were 32.2% for telcagepant 50 mg, 32.0% for telcagepant 150 mg, 36.2% for telcagepant 300 mg, and 32.2% for placebo.CONCLUSIONS:This study confirmed previous findings that telcagepant 300 mg was effective at relieving pain and other migraine symptoms at 2 hours and providing sustained pain freedom up to 24 hours. In this study, telcagepant 150 mg was also effective. Telcagepant was generally well tolerated.